William J. Davis

Interaction between nutrition and theophylline metabolism in children.

Summary: The influences on theophylline metabolism are multifactorial, resulting in significant inter- and intrapatient variability in drug responsiveness. Clinical investigations with adult patients have demonstrated the influence of diet on theophylline metabolism following a single drug dose. We have undertaken this study to examine the effect of nutritional factors on theophylline pharmacokinetics in 14 asthmatic children receiving the drug on a chronic basis. For 12-day periods each patient received three separate diets with different proportions of protein and carbohydrate but with constant fat and caloric intake. Significant differences were detected for theophylline half-life, apparent volume of distribution, and metabolic clearance rate. The high-protein diet markedly shortened the drug-elimination half-life relative to a normal diet, and high carbohydrate significantly increased it (both p < 0.001). Other kinetic parameters confirmed this pattern. Our findings in children clearly establish that nutritional factors have a significant environmental influence on theophylline metabolism during the drugs steady-state pharmacokinetics.

Fenoterol dose-response study in children with asthma

We have studied the effect of fenoterol, a selective beta-2 adrenergic agent, on airway obstruction in children with asthma. The drug was administered orally in single doses of 2.5, 5, and 7.5 mg to 20 children with chronic stable asthma of moderate severity. The mean age of the children was 11.6 yr. Pulmonary function tests were performed as baseline at zero time and at intervals over a 6-hour period after drug administration. Onset of action for all doses was within 1 hr with a peak effect noted at 1.5 to 3 hr, and sustained improvement was observed over the entire 6 hr. The doses of 5 mg and 7.5 mg were equally effective in producing significant improvement of pulmonary function compared to 2.5 mg (p less than 0.05). Side effects remained acceptable for all patients. The 5 and 7.5 mg doses produced significant adverse effects that involved the central nervous and musculoskeletal systems, whereas the 7.5 mg dose caused a significant incidence of tachycardia. Our findings indicate: (1) fenoterol is a potent oral bronchodilator for large and small airways in children, (2) the 7.5 mg dose does not achieve any additive effect over a 5 mg dose; and (3) 5 mg is the optimal oral dose of fenoterol for children from age 8 to 12 yr.

1653 PHARMACOKINETICS OF SALIVARY THEOPHYLLINE IN ASTHMATIC CHILDREN

Although salivary theophylline concentrations have been used to monitor therapy and compliance, considerable variation has been noted. To determine whether the factor of time-dependency can account for this variability, we have measured simultaneous saliva (S) and plasma (P) samples between 2 and 6 hours post oral drug administration in a group of 7 asthmatic children aged 10-14 years. Comparison of the S/P ratios of theophylline revealed higher values during the absorption phase (mean 0.72) and lower values during the elimination phase (mean 0.49) (p<0.01). A comparison of free drug fractions in S and P indicated consistently higher levels in S compartment (mean Free S/Free P ratio of 1.79 with range of 1.0 - 2.85), indicating an active transport mechanism. Our data demonstrate a clear time-dependent relationship for theophylline in S corresponding with drug absorption and elimination. We conclude that: 1) salivary levels of theophylline may in part depend on an active transport mechanism; 2) salivary levels should be obtained at fixed time intervals when evaluating their usefulness in monitoring theophylline therapy.

247 DIETARY INFLUENCES ON THEOPHYLLINE PHARMACOKINETICS IN CHILDREN

We have examined the influence of diet on theophylline (T) pharmacokinetics in 14 asthmatic children, receiving chronic oral T. Doses from 4.2-8.8 mg/kg were given in an amount determined to yield therapeutic serum levels. Each patient was placed on 3 separate diets with different proportions of protein and carbohydrate and with constant fat and calories. Sequential serum T levels were obtained following a single oral dose on day 12 of each test diet. T half-life (t½) decreased on high protein (P) diet to a mean of 4.75 hr. compared to 6.76 on normal (N) diet and increased to 18.10 on high carbohydrate (C) diet (both p < .001). The metabolic clearance rate rose from a mean of .045 L/kg/hr on N to .055 on P and decreased to .037 during C (both p < .001). The apparent volume of distribution remained unchanged, except for an increase from .423 L/kg to .988 on C (p < .01). Multiple linear regression function demonstrated t½ differences to correlate significantly only with dietary changes. No abnormal blood chemistries were detected during any test periods. These results clearly show the effect of diet on T pharmacokinetics in children.

A MICROTITER GAS CHROMATOGRAPHIC ASSAY FOR STUDY OF THEOPHYLLINE PHARMACOKINETICS

Therapy of childhood asthma with theophyllines has been controversial and less than optimal because of a variable dose response relationship and unpredictable toxicity. Theophylline plasma concentration appears to correlate directly with pharmacologic effect and toxicity. The standard spectrophotometric (SP) method for theophylline is time consuming, requires large volumes of blood and is inaccurate in the presence of caffeine and other xanthines. An accurate gas chromatographic (GC) assay was developed and compared with the SP method. The GC response was linear from 0.5 to 100μg/ml of plasma. Recovery of theophylline was 95%.Ten children receiving theophylline preparations by oral and intravenous routes were studied. Peak plasma theophylline levels with the SP method ranged from 7.6 to 30.1 μg/ml, mean 18.2 ± 7.6; with the GC method the range was 4.8 to 18.4 μg/ml, mean 11.2 ± 4.6. Caffeine and other xanthine compounds did not interfere with the GC determinations. Assuming a two compartment open system model and first order kinetics, plasma half time (t½) and elimination constants were calculated individually to determine a dose which would insure maximum therapeutic response and avoid toxic symptoms.This rapid, accurate, specific, microtiter gas chromatographic assay has direct application to patient care.